1. Field of Invention
This invention is directed to an improved freeze-drying (lyophilization) process. More specifically the instant invention concerns a freeze-drying process wherein cephalosporins are prepared which are sterile, essentially crystalline and have good storage stability.
2. Prior Art
Freeze-drying is an old and often used process for removing a solvent from a solute. While the process is cumbersome, expensive and slow, it provides a method for removing a solvent without damaging heat labile solutes. Antibiotics and other pharmaceuticals have been processed by freeze-drying procedures for three or more decades and foods, particularly instant coffee, have been prepared by this method for many years. Ordinarily, a solution from which it is desired to recover the solute in a relatively solvent-free state is frozen solid and then subjected to an environment of a high vacuum and the temperature of the environment is raised to provide the units of heat absorbed in the sublimation of the solvent from the frozen solution. The temperature of the environment is kept below that which would result in the meltdown of the frozen solution. In practice, the temperature of the environment is coordinated with the vacuum to produce the highest reasonable sublimation rate, avoiding a melting of the frozen mass.
Water is the solvent generally utilized in a freeze-drying process. Other solvents can be employed but are limited to those which become solid in the range of temperatures which can be practically employed in the process and which will sublime under vacuum.
Although all of the material does not have to be in solution to effectively operate a freeze-drying process, instant coffee being one probable example, this invention is concerned with a process wherein crystalline material is prepared in a freeze-drying procedure from a true solution. In freeze-drying antibiotics and other pharmaceuticals it has been the practice to follow the classic process outlined above; to wit, prepare solution, freeze to solid, subject to high vacuum, add heat, sublime solvent. However, when such a conventional procedure is followed, most cephalosporins come out as amorphous material. A state that is undersirable because, generally, the amorphous powder is not storage stable, even under refrigerated conditions. The basically white amorphous cephalosporin powders quickly begin to deteriorate to a disagreeable yellow. The yellow slowly appears and becomes noticeable in between 4 and 6 weeks at 4.degree. C., and after 6 months at this temperature generally is universal throughout the powder.
The cephalosporins involved in this invention can be recovered from organic solvents, such as ethanol in an essentially crystalline state. These crystals are equally as stable as the crystals prepared by the freeze-drying process of the instant invention.
However, recovering crystals of the cephalosporins for use in sterile ampoule preparations for parenteral administration poses other problems and conditions which are both inefficient, difficult and costly. For example, there is no effective way known to sterilize the crystals of cephalosporins recovered from organic solvents so the entire crystallization process must be carried out in an aseptic environment. In the large and extensive process required to sterilely crystallize the cephalosporins there are many opportunities for the admittance of foreign materials into the crystals which later on will show up as suspended material in a reconstituted ampoule of the antibiotic. No one has yet developed an apparatus for filling dry material into an ampoule which will measure the material going into each ampoule with as good a consistency and precision as can be routinely achieved with liquid filling equipment.
Accordingly, it is an object of this invention to provide a process of freeze drying cephalosporins, selected from the group consisting of cephalothin sodium, cephaloridine betaine, and cefazolin sodium that will result in sterile essentially crystalline cephalosporins for parenteral administration.
Another object of this invention is to provide a process which will include the sterile liquid filling of a measured volume of a sterile solution of a known concentration of a cephalosporin into an ampoule wherein such cephalosporin is recovered from such solution as an essentially crystalline material for parenteral administration which is storage stable.
Still another object of this invention is to provide an ampoule containing an essentially crystalline cephalosporin which is storage stable and which upon reconstitution for parenteral administration is substantially free of foreign suspended material.